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02 Emerging Methods in Molecular Biology and Genetics

02 Emerging Methods in Molecular Biology and Genetics

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Published by Piotor.Ar
ACNP - Neuropsychopharmacology: 5th Generation of Progress. Section 2/13
ACNP - Neuropsychopharmacology: 5th Generation of Progress. Section 2/13

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Published by: Piotor.Ar on Dec 04, 2009
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01/12/2013

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S E C T I O N
IIEmerging Methods inMolecular Biology andGenetics
SAMUEL H. BARONDES
 When the American College of Neuropsychopharmacology  was founded in the mid-1950s, molecular biology and ge-netics were in their infancy and had little to offer neuropsy-chopharmacology. By 1967, when the first volume in thisseries was published, it still had not become apparent how greatly our field would be influenced by research on genesand on DNA. Of more than a hundred papers in thatvolume—
Psychopharmacology: A Review of Progress 1957–1967 
—only a few used tools of molecular biology.None of those papers, including my own, envisioned thecentral role that such tools have now come to play.This central role, which is documented in this section,istheresult ofthedevelopment oftwotypesofnewtechnol-ogies. One of them, the automated sequencing of the nu-cleotides in DNA, facilitated the decoding of the structureof all genes, including those that make up the human ge-nome. The other consists of ways to manipulate the struc-ture of individual genes in isolated cells or in intact organ-isms, and to measure their levels of expression. This made itpossible to directly study the biological actions of particulargenes, and the effects of changes in their regulatory regionsand coding regions.These technologic advances are now being applied to a
Samuel H. Barondes:
Center for Neurobiology and Psychiatry, Depart-ment of Psychiatry, University of California–San Francisco, San Francisco,California 94143-0984.
Neuropsychopharmacology: The Fifth Generation of Progress.
Edited by Kenneth L. Davis, Dennis Charney, Joseph T. Coyle, andCharles Nemeroff. American College of Neuropsychopharmacology 
2002.
variety of problems in neuropsychopharmacology. For ex-ample, measurements of the levels of expression of largenumbers ofgenes invarious brainregions and nerve cellsareproviding information about the molecular basis of normalbrain functions, and the effects of drugs on these functions.The same technologies are also being used to learn aboutthe molecular pathogenesis of mental disorders. As work onthe human genome continues it will lead to the identifica-tion of gene variants that influence susceptibility to mentaldisorders, as well as of gene variants that influence the alter-native ways that individuals respond to particular psychiat-ric drugs. It will also provide new targets for the creationof better drugs, with greater efficacy and specificity.The six chapters in this section provide a sampling of themolecular and genetic tools that are being used to advanceneuropsychopharmacology. Because these tools are chang-ing so rapidly, the authors provide overviews rather thanextensive details. In this way they hope to make these toolscomprehensible to the nonspecialist, and to invite their fur-ther application. As you read these overviews you will become increasingly familiar with a series of new terms—from
gene chips 
,
knock-outs 
, and
viral vectors 
, to
genome scans 
and
pharmacogenetics 
.These terms are becoming commonplace, and are already scatteredthroughoutthisbook.Bythetimethenextvolumein this series appears, it is likely that the methods that they refer to will be so widely used in our field that a separatesection about them will no longer be needed.
 
 18
USING HUMAN GENOMICSTO ADVANCENEUROPSYCHOPHARMACOLOGY 
L. ALISON MCINNESNELSON B. FREIMER
Genomics, the study of genomes, includes gene mapping,sequencing, and investigation of gene functions. This field willadvanceneuropsychopharmacologyintwocomplemen-tary ways. First, it is hoped that application of genomicstechnologies to pedigree and population samples of patients with psychiatric disorders will allow the identification of genes contributing to the etiology and pathogenesis of thesediseases and provide a rational basis for new drug develop-ment. Second, variations in the sequence of known genes whoseproductsarethetargetsofcurrentpsychotropicdrugsmay influence the likelihood that an individual patient willhave a therapeutic response to these drugs or experience aside effect. Identification and functional characterization of these sequence variants in large populations of patients of various ethnicities constitutes the discipline of pharmaco-genomics. The scope of psychopharmacogenomics, how-ever, is currently restricted by our limited knowledge of thegenes that contribute to psychiatric disorders and the neuralpathways altered by psychotropic agents. Fortunately, dataand technologies provided by the U.S. Human GenomeProject (HGP), including provision of the complete se-quence of the human genome, will greatly facilitate identifi-cation of such genes (1,2). This chapter describes how tech-nologic advances in genomics will shape the future of psychiatric genetics and psychopharmacogenomics, fieldsthat may establish an objective basis for the restructuringof the nosology, diagnosis, and treatment of psychiatric dis-orders.Theresultsofgeneticstudiesofparticularpsychiatricdisorders and of responses to specific drugs are consideredin other parts of this book.
L. A. McInnes and Nelson B. Freimer:
Department of Psychiatry andNeurogenetics Laboratory, University of California–San Francisco, San Fran-cisco, California 94143.
IDENTIFYING GENES FOR PSYCHIATRICDISORDERS
Rational strategies for the advancement of psychopharma-cology are dependent on furthering our currently sparseknowledge of the pathophysiologic basis of psychiatric dis-orders. To this end, human genetic approaches offer apromising alternative to traditional biochemical and neuro-physiologic investigations as twin, family, and adoptionstudies all support the heritability of many psychiatric syn-dromes. Unfortunately, attempts to first map (i.e., localizea uniqueregion ofDNA shared bypatients with aparticulardisorder)and thenidentifygenespredisposingtopsychiatricdisorders have been frustrated by the complexity of the ge-netic mechanisms underlying behavioral phenotypes. A phenotype is the observable physical manifestation of genetic variation at a particular site or locus in the DNA, whereas a genotype refers to the actual DNA sequence, atthe responsible genetic locus. With single gene disorders(also referred to as mendelian disorders) there is a simple,direct relationship between variation in a single gene andthe phenotype that results. Thus, all patients with a givenmendelian disorder, such as cystic fibrosis, will carry abnor-mal genotypes at a single disease locus. In contrast, the rela-tionshipbetweenphenotypeandgenotypeisnotstraightfor- ward for complex genetic traits. In this setting, multipledifferent susceptibility genes and environmental factors in-teract in varying combinations within individuals who ap-pear to have clinically indistinguishable phenotypes. Thismeans that in any given sample of patients diagnosed witha particular psychiatric disorder, the number of individualsactually sharing a disease gene or genes in common mightbe very small such that the ‘‘effective’’ sample size does notprovide enough power to detect the responsible genes.Fortunately,therearestrategiesforfindinggenescontrib-uting to complex traits that have been successfully appliedto the genetic dissection of other nonpsychiatric, genetically 

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